Synthetic Studies on Oligomycins. Synthesis of the Oligomycin B Spiroketal and Polypropionate Portions

Abstract

The oligomycin B spiroketal portion, [2S,2(2R),3S,6R,8S,8(3R),9S,10R,11S]-2-[2-(t-butyldiphenylsilyloxy)propyl]-8-[3-(hydroxymethyl)pentyl]-3,9,11-trimethyl-1,7-dioxaspiro[5.5]undecane-5,10-diol (2), and polypropionate portion, ethyl (2E,4S,5R,6R,7S,8S,9R,10S,12R,13S,14R,16E)-5-(t-butyldimethylsilyloxy)7,9-(isopropylidenedioxy)-12,13-(4-methoxybenzylidenedioxy)-4,6,8,10,12,14-hexamethyl-11-oxo-18-phenylsulfonyloctadeca-2,16-dienoate (3), have been synthesized. The C19-C21 Wittig salt, [(2S,3R)-2-ethyl-3,4-(isopropylidenedioxy)butyl]triphenylphosphonium iodide (6), prepared from 2-butene-1,4-diol via Sharpless epoxidation, was coupled with the C22-C27 aldehyde, benzyl 2,4-dideoxy-3-O-(4-methoxybenzyl)-2,4-di-C-methyl-α,β-l-galacto-hexodialdopyranoside-(1,5) (7), prepared from (Z)-2-butene-1,4-diol via Sharpless epoxidation and the Brown’s crotylboration. The resulting coupling product was transformed to the C19-C27 lactone, [3S,4R,5R,6S,6(3R,4R)]-6-[3-ethyl-4,5-(isopropylidenedioxy)pentyl]-4-(4-methoxybenzyloxy)-3,5-dimethyl-3,4,5,6-tetrahydro-2H-pyran-2-one (4). The C28-C34 organostannane compound, (2R,4S,5S,7RS)-2-(t-butyldiphenylsilyloxy)-5-methyl-7-(tributylstannyl)-4-(triethylsilyloxy)-7-[(2-trimethylsilylethoxy)methoxy]heptane (5b), was prepared from (R)-methyl 3-hydroxybutyrate via the Brown’s crotylboration and the Still’s stannylation. After lithiation of 5b with butyllithium, the resulting α-alkoxy organolithium compound was coupled with 4 and the product was converted to the C19-C34 spiroketal, [2S,2(2R),3S,6R,8S,8(3R,4R),9S,10R,11S]-2-[2-(t-butyldiphenylsilyloxy)propyl]-8-[3-ethyl-4,5-(isopropylidenedioxy)pentyl]-10-(4-methoxybenzyloxy)-3,9,11-trimethyl-1,7-dioxaspiro[5.5]undecan-5-ol (37). The synthetic 2, derived from 37, was identical to the oligomycins (A, B, C mixture) degradation product in all respects, which elucidates the absolute stereochemistry of oligomycin B (1b). The C3-C9 aldehyde, (2-trimethylsilylethoxy)methyl 2,4,6-trideoxy-3-O-(4-methoxybenzyl)-2,4,6-tri-C-methyl-d-glycero-α-l-ido-heptodialdopyranoside-(1,5) (9), was prepared from (2S)-3-(t-butyldimethylsilyloxy)-2-methylpropanal via Keck’s crotylstannane addition and Brown’s crotylboration. The aldol coupling between the zinc enolate of the C10-C16 ketone, t-butyldimethylsilyl 2,3,7,8-tetradeoxy-4-O-(4-methoxybenzyl)-3,5-di-C-methyl-α-l-xylo-octopyranosid-6-ulose (10), prepared from methyl (R)-(+)-lactate via Brown’s crotylboration and a metallated methoxyallene addition, and aldehyde 9 gave the C8-C9 syn, C9-C10 syn product, which was transformed to the oligomycin B polypropionate portion 3 through elongation of the C1-C2 and C17-C18 carbon units.

Distinct Pools of Non-Glycolytic Substrates Differentiate Brain Regions and Prime Region-Specific Responses of Mitochondria

“…As a complementary approach, we supplied synaptosomes with glucose and measured ECAR after blocking oxidative phosphorylation with the addition of oligomycin (Oligo), an inhibitor of ATP synthase (Figure 1B,C) [24]. Oligomycin treatment leads to an increase in ECAR as the use of glycolysis increases to compensate for the loss of ATP generation from oxidation phosphorylation (Figure 1C, glycolytic reserve).…”

Discovery of a Phosphine-Mediated Cycloisomerization of Alkynyl Hemiketals: Access to Spiroketals and Dihydropyrazoles via Tandem Reactions

“…A number of methods for the synthesis of spiroketals have been developed. − They were inspired by the challenge of natural product total synthesis, physical investigations into the fundamental principles governing spiroketal configuration, and the biological activities associated with spiroketal-containing natural products. Representative examples of natural product spiroketals are oligomycin B ( 1 ), − berkelic acid ( 2 ), − and reveromycin A ( 3 ) (Figure ). − Among the structures in Figure , oligomycin B is noteworthy because it contains a ketone α to the spiroketal which parallels the organization of functionality that develops in the new tandem reaction reported here. Activities reported for 1 – 3 include cytotoxicity by inhibition of ATP or protein synthesis, inhibition of proteases such as MMP-3 and caspase-1, and antifungal activity.…”

Regioselective Alkyl and Alkynyl Substitution Reactions of Epoxy Alcohols by the Use of Organoaluminum Ate Complexes: Regiochemical Reversal of Nucleophilic Substitution Reactions

“…The present work is the first protocol of this type of transformation except for organocopper reagents. Although the reactions of epoxy alcohols 4 and 5 with dimethylcupurate have been widely used in the synthesis of various natural products, e.g., tautomycin, ingramycin, olygomycin, rodularin, FK-506, etc., their stereoselectivity and chemical yields were not always satisfactory. Therefore, this new methodology provides an extremely useful tool for natural product synthesis.…”